Methods for treating complement-mediated diseases

Abstract

Provided herein are methods of treating cold agglutinin disease (CAD) or chronic inflammatory demyelinating polyneuropathy (CIDP) in a subject in need thereof. The methods comprise administering to a subject a humanized antibody that specifically binds complement component C1s (anti-C1s antibody). Methods of treating CAD comprise administering the anti-C1s antibody to a subject in a fixed dose. Methods of treating CIDP comprise administering to a subject a weight-based loading dose of the anti-C1s antibody followed by one or more fixed maintenance doses. The methods comprise administering an effective dose of anti-C1s antibody to achieve a minimum level of CP inhibition for therapeutic effect.

1 . A method for treating cold-agglutinin disease in a subject in need thereof, comprising administering to the subject about 3.5 g of a humanized antibody that specifically binds complement component C1s, wherein the antibody comprises a light chain (LC) complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain (HC) CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 6. 
     
     
         2 . The method of  claim 1 , wherein the antibody is administered about every 10, 12, 14, or 16 weeks. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein about 3.5 g of the antibody is administered about 4 weeks after the first dose. 
     
     
         5 . The method of  claim 1 , wherein the antibody is administered intravenously or subcutaneously. 
     
     
         6 . The method of  claim 1 , wherein about 3.5 g of the antibody is administered intravenously on Day 1 and about every 10, 12, 14, or 16 weeks thereafter, and about 3.5 g of the antibody is additionally administered intravenously on or about Day 29. 
     
     
         7 . The method of  claim 1 , wherein about 3.5 g of the antibody is administered intravenously on Day 1 and about every 12 weeks thereafter, and about 3.5 g of the antibody is additionally administered intravenously on or about Day 29. 
     
     
         8 . The method of  claim 1 , wherein administration of the antibody:
 (i) increases the level of hemoglobin in the subject;   (ii) decreases the level of bilirubin in the subject;   (iii) inhibits the classical complement pathway activity by about 90% or greater, as determined by measuring the amount of the terminal complement complex, C5b-9; and/or   (iv) decreases the 50% hemolytic complement activity (CH50) level to less than about 10 IU/mL.   
     
     
         9 .- 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein following administration of the antibody, the subject has a plasma concentration of the antibody of at least about 100 μg/mL. 
     
     
         13 .- 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the antibody comprises a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 8. 
     
     
         17 . The method of  claim 1 , wherein the antibody is a Fab fragment, a F(ab′)2 fragment, a scFv, or a Fv. 
     
     
         18 . The method of  claim 1 , wherein the antibody comprises a heavy chain constant region of the isotype IgG4. 
     
     
         19 . The method of  claim 18 , wherein the IgG4 constant region comprises a proline substitution, a glutamic acid substitution, a leucine substitution, and a serine substitution at amino acid residues 108, 115, 308, and 314, respectively, relative to the IgG4 constant region sequence of SEQ ID NO: 11. 
     
     
         20 . The method of  claim 1 , wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10. 
     
     
         21 . A method for treating chronic inflammatory demyelinating polyneuropathy (CIDP) in a subject in need thereof, comprising administering to the subject a loading dose of about 50 mg/kg of the subject's body weight of a humanized antibody that specifically binds complement component C1s, and one or more maintenance doses of about 300 mg, about 600 mg, about 1200 mg, about 2400 mg, about 3600 mg, or about 7200 mg of the antibody, wherein the antibody comprises a light chain (LC) complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain (HC) CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 6. 
     
     
         22 . The method of  claim 21 , wherein the one or more maintenance doses are administered about every 1, 2, 4, or 12 weeks thereafter. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 21 , wherein the loading dose is administered intravenously on Day 1, followed by subcutaneous administration of the maintenance dose about every week starting on Day 8. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 21 , wherein the subject has received another CIDP treatment within about one week of the loading dose or is concomitantly receiving another CIDP treatment. 
     
     
         27 . The method of  claim 21 , wherein the subject has not received another treatment for CIDP within about 6 months prior to the loading dose. 
     
     
         28 .- 33 . (canceled) 
     
     
         34 . The method of  claim 21 , wherein the antibody comprises a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 8. 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 21 , wherein the antibody comprises a heavy chain constant region of the isotype IgG4. 
     
     
         37 .- 38 . (canceled)